Activins and their antagonists the inhibins play a critical role in regulating the pituitary gonadal axis. Betaglycan (BG) binds inhibin and facilitates antagonism of activin by inhibin. Lefry proteins are structurally related to activins and inhibins and have been hypothesized to antagonize type II activin receptors. The long term objectives of this project are to further understand the mechanisms and physiological importance of antagonism correlates with loss of reproductive function. In Specific Aim I of this proposal, mutational analysis of BG will be used to define the functional binding site(s) on this proteoglycan for inhibin. Specific Aim II includes over-expression and targeted disruption experiments intended to further characterize the physiological importance of BG as an inhibin receptor in intact cells. Finally, experiments outlined in Specific Aim III will test whether Lefty proteins compete with activin for binding to ActRII and if they are involved in antagonism of activin signals in reproductive cell types. Together, these experiments will further elucidate mechanisms of activating antagonism to provide a basis for the development of tools and reagents to treat pituitary and reproductive disorders.